Pubmed Highlight: silencing the extra copy of chromosome 21 in Down’s syndrome cells using the XIST gene

Having been been part in 1991 of the team who originally cloned the mouse Xist gene, I've been really excited by the news. Scientists at the University of Massachusetts discovered that XIST, the gene involved in X-chromosome inactivation, can be used to turn off the extra chromosome 21 in Down syndrome.

The study has been published on the latest issue of Nature.

Nature. 2013 Jul 17. doi: 10.1038/nature12394.

Translating dosage compensation to trisomy 21.

Jiang J, Jing Y, Cost GJ, Chiang JC, Kolpa HJ, Cotton AM, Carone DM, Carone BR, Shivak DA, Guschin DY, Pearl JR, Rebar EJ, Byron M, Gregory PD, Brown CJ, Urnov FD, Hall LL, Lawrence JB.

Source

Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.

Abstract

Down's syndrome is a common disorder with enormous medical and social costs, caused by trisomy for chromosome 21. We tested the concept that gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, XIST (the X-inactivation gene). Using genome editing with zinc finger nucleases, we inserted a large, inducible XIST transgene into the DYRK1A locus on chromosome 21, in Down's syndrome pluripotent stem cells. The XIST non-coding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosome-wide transcriptional silencing and DNA methylation to form a 'chromosome 21 Barr body'. This provides a model to study human chromosome inactivation and creates a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing one chromosome 21. Successfultrisomy silencing in vitro also surmounts the major first step towards potential development of 'chromosome therapy'.

PMID:

 

23863942